1. Field of the Invention
This invention relates to novel pyrrolo[2,3-d]pyrimidine derivatives which are useful as antitumor agents.
2. Prior Art
Folic acid is a carrier of a C1 unit in a living body, derived from formic acid or formaldehyde, acting as a coenzyme in various enzymatic reactions such as those in biosynthesis of nucleic acid, in .metabolism of amino acids and peptides and in generation of methane. Particularly in the biosynthesis of nucleic acid, folic acid is essential for formylation in the two pathways, i.e. the purine synthetic pathway and the thymidine synthetic pathway. Usually folic acid is required to be transformed into its activated coenzyme form by reduction in two steps before it becomes biologically active.
Amethopterin (methotrexate; MTX) and related compounds are known to inhibit the reduction from dihydrofolic acid to tetrahydrofolic acid by coupling strongly with the dominant enzyme in the second step (dihydrofolic acid reductase). These drugs have been developed as antitumor drugs because they may disturb the DNA synthesis and consequently cause cell death, and are currently regarded as of major clinical importance.
On the other hand, a novel tetrahydroaminopterin antitumor agent (5,10-dideaza-5,6,7,8-tetrahydroaminopterin: DDATHF) has been reported which, unlike the drugs described above, does not inhibit dihydrofolic acid reductase and the main mechanism of which consists in inhibition of glycinamide ribonucleotide transformylase required in the initial stage of purine biosynthesis [Journal of Medicinal Chemistry, 28, 914(1985)].
With regard to the treatment of cancer, it is now strongly expected to develop a new drug which possesses an excellent effect based on a novel mechanism and exhibits a highly selective toxicity against cancer cells. An antitumor agent which mainly antagonizes folic acid, namely, MTX is now widely used in a clinical field, but it is not sufficient due to its relatively high toxicity and insufficient effect on solid tumors. And further, increase of resistance against this type of drug is a big problem.
Thus, some new series of compounds as antitumor agents have been proposed [see European Patent Application No. 0 334 636 (pyrrolopyrimidine derivatives), U.S. Pat. Nos. 4,532,241 and 4,684,653 (Pyridopyrimidine derivatives)] and European Patent Application No. 90110131.1.